Electrode band system and methods of using the system to treat obesity

ABSTRACT

At least one of a plurality of disorders of a patient characterized at least in part by vagal activity innervating at least one of a plurality of organs of the patient is treated by a method that includes positioning an electrode on a vagus nerve. An electrical signal is applied to the electrode to modulate vagal activity by an amount selected to treat the disorder. In some embodiments, the disorder is obesity. The signal may be a blocking or a stimulation signal. In some embodiments, the signal is selected to, at least in part, downregulate neural activity on the vagus nerve.

I. CROSS-REFERENCE TO RELATED APPLICATION

The present application is a continuation of U.S. patent applicationSer. No. 13/758,223, filed Feb. 4, 2013, which is a continuation of U.S.patent application Ser. No. 13/178,221, filed Jul. 7, 2011, now U.S.Pat. No. 8,369,952, which is a continuation of U.S. patent applicationSer. No. 11/656,121, filed Jan. 22, 2007, now U.S. Pat. No. 7,986,995,which is a continuation of U.S. patent application Ser. No. 10/752,944,filed Jan. 6, 2004, now U.S. Pat. No. 7,167,750, which is acontinuation-in-part application of the following U.S. patentapplications, all filed on Sep. 29, 2003: U.S. patent application Ser.No. 10/674,330, now U.S. Pat. No. 7,489,969; U.S. patent applicationSer. No. 10/675,818, now abandoned, and U.S. patent application Ser. No.10/674,324, now abandoned. The aforementioned patent applications arecontinuation-in-part applications of U.S. patent application Ser. No.10/358,093, filed Feb. 3, 2003, now abandoned. The present applicationalso claims priority to the aforesaid Serial No. 10/358,093.

II. BACKGROUND OF THE INVENTION

Field of the Invention

This invention pertains to treatments of disorders associated, at leastin part, with neural activity. These may include, without limitation,gastrointestinal, pancreo-biliary, cardio-respiratory and centralnervous system disorders (including neurological and psychiatric,psychological and panic disorders). More particularly, this inventionpertains to treatment of such disorders through management of neuralimpulse stimulation and blocking.

Description of the Prior Art

A. Functional Gastrointestinal Disorders (FGIDs)

Functional Gastrointestinal Disorders (FGIDs) are a diagnostic groupinghaving diagnostic criteria based on symptomatology, because thepathophysiology of these diseases is multifactorial with somepathophysiologic mechanisms in common. FGIDs are thought to be due toaltered autonomic nervous system balance and to be pathophysiologicalcombinations of: (1) abnormal GI motility; (2) visceralhypersensitivity; and, (3) brain-gut interactions. Tougas, “TheAutonomic Nervous System in Functional Bowel Disorders”, Gut, Vol. 47(Suppl IV), pp. iv78-iv80 (2000) and Drossman, “Rome II: A MultinationalConsensus Document on Gastrointestinal Disorders—The FunctionalGastrointestinal Disorders and the Rome II Process”, Gut, Vol. 45 (SupplII):II1-II5 (1999). The FGIDs of interest to the present invention arefunctional dyspepsia (dysmotility-like) and irritable bowel syndrome(IBS).

1. Functional Dyspepsia (Dysmotility-Like)

Functional dyspepsia (dysmotility-like), is diagnosed when a patient'ssymptoms, in the absence of other organic disease likely to explain thesymptoms, include persistent or recurrent pain or discomfort centered inthe upper abdomen that may be accompanied by upper abdominal fullness,early satiety, bloating or nausea. Talley et al., “Rome II: AMultinational Consensus Document on GastrointestinalDisorders—Functional Gastroduodenal Disorders” Gut, Vol. 45 (Suppl II),pp. I37-II42 (1999).

A spectrum of dysmotilities has been documented in patients withfunctional dyspepsia. These include delayed gastric emptying of solidsand liquids, reduced vagal tone, gastric dysrhythmias and impairedgastric accommodation. Furthermore, some studies have found goodcorrelation between symptoms and indices of dysmotility, while othershave not. Stanghellini V, et al., “Delayed Gastric Emptying of Solids inPatients with Functional Dyspepsia”, Gastroenterol, (1996)110:1036-1042. Undeland K A, et al., “Wide Gastric Antrum and Low VagalTone in Patients with Diabetes Mellitus Type 1 Compared to Patients withFunctional Dyspepsia and Healthy Individuals”, Dig Dis Sci, (1996)41:9-16. Tack J, et al., “Role of Impaired Gastric Accommodation to aMeal in Functional Dyspepsia”, Gastroenterol, (1998) 115:1346-1352.Wilmer A, et al., “Ambulatory Gastrojejunal Manometry in SevereMotility-like Dyspepsia: Lack of Correlation between Dysmotility,Symptoms and Gastric Emptying”, Gut, (1998) 42:235-242. Tack J, et al.,“Symptom Pattern and Gastric Emptying Rate Assessed by the Octanoic AcidBreath Test in Functional Dyspepsia” [abstract]. Gastroenterol, (1998)114:A301. Cuomo R, et al., “Functional Dyspepsia Symptoms, GastricEmptying and Satiety Provocation Test: Analysis of Relationships”, ScandJ Gastroenterol, (2001) 36:1030-1036. Sarnelli G, et al., “SymptomsAssociated with Impaired Gastric Emptying of Solids and Liquids inFunctional Dyspepsia”, Am J Gastroenterol, (2003) 98:783-788.

2. Irritable Bowel Syndrome (IBS)

The second FGID of interest, IBS, is diagnosed when a patient's symptomsinclude persistent abdominal pain or discomfort, in the absence of otherexplanatory organic disease, along with at least two of the following:relief of pain with defecation, onset of symptoms associated with achange in frequency of stools and/or onset of symptoms associated with achange in appearance/form of stools. Thompson W G, et al., “Rome II: AMultinational Consensus Document on GastrointestinalDisorders—Functional Bowel Disorders and Functional Abdominal Pain”,Gut, (1999); 45(Suppl II):II43-II47.

In addition to colonic dysmotility, a number of other GI motilityabnormalities have been identified, including delayed gastric emptying,gastroparesis, and small intestine motility abnormalities. Vassallo M J,et al., “Colonic Tone and Motility in Patients with Irritable BowelSyndrome”, Mayo Clin Proc, (1992); 67:725-731. Van Wijk H J, et al.,“Gastric Emptying and Dyspeptic Symptoms in the Irritable BowelSyndrome”, Scand J Gastroenterol, (1992); 27:99-102. Evans P R, et al.,“Gastroparesis and Small Bowel Dysmotility in Irritable Bowel Syndrome”,Dig Dis Sci (1997); 42:2087-2093. Cann P A, et al. “Irritable BowelSyndrome: Relationship of Disorders in the Transit of a Single SolidMeal to Symptoms Patterns”, Gut, (1983); 24:405-411. Kellow J E, et al.,“Dysmotility of the Small Intestine in Irritable Bowel Syndrome”, Gut,(1988); 29:1236-1243. Evans P R, et al., “Jejunal SensorimotorDysfunction in Irritable Bowel Syndrome: Clinical and PsychosocialFeatures”, Gastroenterol, (1996); 110:393-404. Schmidt T, et al.,“Ambulatory 24-Hour Jejunal Motility in Diarrhea-Predominant IrritableBowel Syndrome”, J Gastroenterol, (1996); 31:581-589. Simren M, et al.,“Abnormal Propagation Pattern of Duodenal Pressure Waves in theIrritable Bowel Syndrome (IBS)”, Dig Dis Sci, (2000); 45:2151-2161.

A related finding is that patients with constipation-predominant IBShave evidence of decreased vagal tone, while diarrhea-predominant IBS isassociated with evidence of increased sympathetic activity. Aggarwal A,et al., “Predominant Symptoms in Irritable Bowel Syndrome Correlate withSpecific Autonomic Nervous system Abnormalities”, Gastroenterol, (1994);106:945-950.

There is no cure for IBS. Treatments include supportive palliative care(antidiarrheals, dietary modification and counseling).

A recently approved drug to treat selected patients with FGIDs istegaserod maleate sold under the tradename “Zelnorm®” by NovartisPharmaceuticals Corp., East Hanover, N.J., USA. The product literatureon Zelnorm recognizes the enteric nervous system is a key element intreating IBS. The literature suggests Zelnorm® acts to enhance basalmotor activity and to normalize impaired motility. Novartis productdescription, Zelnorm®, July 2002 (T2002-19). Zelnorm's approved use islimited to females with constipation-related IBS. It is for short-termuse only.

B. Gastroparesis

The third disease indication discussed here, gastroparesis (or delayedgastric emptying) is associated with upper GI symptoms such as nausea,vomiting fullness, bloating and early satiety. Gastroparesis can becaused by many underlying conditions. The most important, because ofchronicity and prevalence, are diabetes, idiopathic and post-surgical.Hornbuckle K, et al. “The Diagnosis and Work-Up of the Patient withGastroparesis”, J Clin Gastroenterol, (2000); 30:117-124. GI dysmotilityin the form of delayed gastric emptying is, by definition, present inthese patients.

In patients with Type 1 diabetes mellitus and delayed gastric emptying,there appears to be a relationship between delayed gastric emptying andlow vagal tone. Merio R, et al., “Slow Gastric Emptying in Type 1Diabetes: Relation to Autonomic and Peripheral Neuropathy, BloodGlucose, and Glycemic Control”, Diabetes Care, (1997); 20:419-423. Arelated finding is that patients with Type 1 diabetes have low vagaltone in association with increased gastric antral size, possiblycontributing to the dysmotility-associated symptoms seen in thesepatients. Undeland K A, et al., “Wide Gastric Antrum and Low Vagal Tonein Patients with Diabetes Mellitus Type 1 Compared to Patients withFunctional Dyspepsia and Healthy Individuals”, Dig Dis Sci, (1996);41:9-16.

The current treatments for gastroparesis are far from satisfactory. Theyinclude supportive care, such as dietary modification, prokinetic drugs,and; when required, interventions such as intravenous fluids andplacement of a nasogastric tube may be needed.

C. Gastroesophageal Reflux Disease (GERD)

The fourth indication, GERD, can be associated with a wide spectrum ofsymptoms, including dyspepsia, reflux of gastric contents into themouth, dysphagia, persistent cough, refractory hyperreactive airwaydisease and even chronic serous otitis media. Sontag S J, et al.,“Asthmatics with Gastroesophageal Reflux: Long Term Results of aRandomized Trial of Medical and Surgical Antireflux Therapies”, Am JGastroenterol, (2003); 98:987-999. Poelmans J, et al., “ProspectiveStudy on the Incidence of Chronic Ear Complaints Related toGastroesophageal Reflux and on the Outcome of Antireflux Therapy”, AnnOtol Rhinol Laryngol, (2002); 111:933-938.

GERD is considered to be a chronic condition for which long-term medicaltherapy and/or surgical therapy is often deemed necessary, insignificant part because esophageal adenocarcinoma is sometimes aconsequence of GERD. DeVault K R, et al., “Updated Guidelines for theDiagnosis and Treatment of Gastroesophageal Reflux Disease”, Am JGastroenterol, (1999); 94:1434-1442. Lagergren J, et al., “SymptomaticGastroesophageal Reflux as a Risk Factor for Esophageal Adenocarcinoma”,New Engl J Med, (1999); 340:825-831.

The underlying pathophysiological mechanisms in GERD are considered tobe transient lower esophageal relaxations (TLESRs) in the presence ofeither an inadequate pressure gradient between the stomach and theesophagus across the lower esophageal sphincter and/or low amplitudeesophageal activity at times when gastric contents do reflux into theesophagus. In addition, gastric distention is thought to be associatedwith an increase in TLESRs. Mittal R K, et al., “Mechanism of Disease:The Esophagogastric Junction”, New Engl J Med, (1997); 336:924-932.Scheffer R C, et al., “Elicitation of Transient Lower OesophagealSphincter Relaxations in Response to Gastric Distension”,Neurogastroenterol Motil, (2002); 14:647-655.

GERD is generally considered to be the result of a motility disorderwhich permits the abnormal and prolonged exposure of the esophageallumen to acidic gastric contents. Hunt, “The Relationship Between TheControl Of pH And Healing And Symptom Relief In Gastro-OesophagealReflux Disease”, Ailment Pharmacol Ther., 9 (Suppl. 1) pp. 3-7 (1995).Many factors are believed to contribute to the onset of GERD. Theseinclude transient lower esophageal sphincter relaxations (as previouslydescribed), decreased LES resting tone, delayed stomach emptying and anineffective esophageal clearance.

Certain drugs have had some effectiveness at controlling GERD but failto treat underlying causes of the disease. Examples of such drugs areH₂-receptor antagonists (which control gastric acid secretion in thebasal state) and proton pump inhibitors (which control meal-stimulatedacid secretion). Hunt, id. Both classes of drugs can raise intragastricpH to or about 4 for varying durations. Hunt, supra.

Surgery treatments are also employed for the treatment of GERD andinclude techniques for bulking the lower esophageal sphincter such asfundoplication and techniques described in U.S. Pat. No. 6,098,629Johnson et al, Aug. 8, 2000. Other surgical techniques include placementof pacemakers for stimulating muscle contractions in the esophagealsphincter, the stomach muscles or in the pyloric valve. U.S. Pat. No.6,104,955 to Bourgeois, U.S. Pat. No. 5,861,014 to Familoni.

A summary of GERD treatments can be found in DeVault, et al., “UpdatedGuidelines for the Diagnosis and Treatment of Gastroesophageal RefluxDisease”, Amer. J. of Gastroenterology, Vol. 94, No. 6, pp. 1434-1442(1999).

Notwithstanding multiple attempts at various types of treatment, GERDcontinues to be a serious disease proving to be difficult to treat byany of the foregoing prior art techniques. In view of the foregoing andnotwithstanding various efforts exemplified in the prior art, thereremains a need for an effective treatment for GERD. It is an object ofthe present invention to provide a novel treatment and novel apparatusfor the treatment of GERD.

D. Electrical Stimulation to Treat GI Disorders

Treatment of gastrointestinal diseases through nerve stimulation havebeen suggested. For example, U.S. Pat. No. 6,238,423 to Bardy dated May29, 2001 describes a constipation treatment involving electricalstimulation of the muscles or related nerves of the gut. U.S. Pat. No.6,571,127 to Ben-Haim et al. dated May 27, 2003 describes increasingmotility by applying an electrical field to the GI tract. U.S. Pat. No.5,540,730 to Terry, Jr. et al., dated Jul. 30, 1996 describes a motilitytreatment involving vagal stimulation to alter GI contractions inresponse to a sense condition indicative of need for treatment. The '730patent also uses a definition of dysmotility more restrictive than inthe present application. In the '730 patent, dysmotility is described ashyper- or hypo-contractility. In the present application, dysmotility isa broader concept to refer to all abnormalities of gastric emptying orbowel transfer regardless of cause. U.S. Pat. No. 6,610,713 to Traceydated Aug. 26, 2003 describes inhibiting release of a proinflammatorycytokine by treating a cell with a cholinergic agonist by stimulatingefferent vagus nerve activity to inhibit the inflammatory cytokinecascade.

A substantial body of literature is developed on nerve stimulation. Forexample, in Dapoigny et al., “Vagal influence on colonic motor activityin conscious nonhuman primates”, Am. J. Physiol., 262:G231-G236 (1992),vagal influence on colonic motor activity was investigated in consciousmonkeys. To block antidromic interference, the vagus was blocked viavagal cooling and a vagal stimulation electrode was implanted distal tothe vagal block. It was noted that vagal efferent stimulation increasedcontractile frequency and that the vagus has either a direct or indirectinfluence on fasting and fed colonic motor activity throughout thecolon, and that a non-adrenergic, noncholinergic inhibitory pathway isunder vagal control.

Colonic and gastric stimulation are also described in a number ofarticles associated with M. P. Mintchev. These include: Mintchev, etal., “Electrogastrographic impact of multi-site functional gastricelectrical stimulation”, J. of Medical Eng. & Tech., Vol. 23, No. 1, pp.5-9 (1999); Rashev, et al., “Three-dimensional static parametricmodeling of phasic colonic contractions for the purpose ofmicroprocessor-controlled functional stimulation”, J. of Medical Eng. &Tech., Vol. 25, No. 3 pp. 85-96 (2001); Lin et al., “Hardware-softwareco-design of portable functional gastrointestinal stimulator system”, J.of Medical Eng. & Tech., Vol. 27, No. 4 pp. 164-177 (2003); Amaris etal., “Microprocessor controlled movement of solid colonic content usingsequential neural electrical stimulation”, Gut, 50: pp 475-479 (2002)and Rashev et al., “Microprocessor-Controlled Colonic Peristalsis”,Digestive Diseases and Sciences, Vol. 47, No. 5, pp. 1034-1048 (2002).

The foregoing references describe nerve stimulation to stimulatemuscular contraction in the GI tract. As will be more fully discussed,the present invention utilizes vagal stimulation to improve vagal tone(similar in concept to improving cardiac electrical tone through cardiacpacing) and/or to treat GI disorders by altering the nature of duodenumcontents by stimulation pancreatic and biliary output. The invention isalso applicable to treating other diseases such as neuropsychiatricdisorders.

Vagal tone has been shown to be associated with dyspepsia. Hjelland, etal., “Vagal tone and meal-induced abdominal symptoms in healthysubjects”, Digestion, 65: 172-176 (2002). Also, Hausken, et al., “LowVagal Tone and Antral Dysmotility in Patients with FunctionalDyspepsia”, Psychosomatic Medicine, 55:12-22 (1993). Also, decreasedvagal tone has been associated with irritable bowel syndrome.Heitkemper, et al., “Evidence for Automatic Nervous System Imbalance inWomen with Irritable Bowel Syndrome”, Digestive Diseases and Sciences,Vol. 43, No. 9, pp. 2093-2098 (1998).

Also, as will be discussed, the present invention includes, in severalembodiments, a blocking of a nerve (such as the vagal nerve) to avoidantidromic influences during stimulation. Cryogenic nerve blocking ofthe vagus is described in Dapoigny et al., “Vagal influence on colonicmotor activity in conscious nonhuman primates”, Am. J. Physiol.,262:G231-G236 (1992). Electrically induced nerve blocking is describedin Van Den Honert, et al., “Generation of Unidirectionally PropagatedAction Potentials in a Peripheral Nerve by Brief Stimuli”, Science, Vol.206, pp. 1311-1312. An electrical nerve block is described in Solomonow,et al., “Control of Muscle Contractile Force through IndirectHigh-Frequency Stimulation”, Am. J. of Physical Medicine, Vol. 62, No.2, pp. 71-82 (1983) and Petrofsky, et al., “Impact of Recruitment Orderon Electrode Design for Neural Prosthetics of Skeletal Muscle”, Am. J.of Physical Medicine, Vol. 60, No. 5, pp. 243-253 (1981). A neuralprosthesis with an electrical nerve block is also described in U.S.Patent Application Publication No. US 2002/0055779 A1 to Andrewspublished May 9, 2002. A cryogenic vagal block and resulting effect ongastric emptying are described in Paterson C A, et al., “Determinants ofOccurrence and Volume of Transpyloric Flow During Gastric Emptying ofLiquids in Dogs: Importance of Vagal Input”, Dig Dis Sci, (2000);45:1509-1516.

III. SUMMARY OF THE INVENTION

A method and apparatus for treating at least one of a plurality ofdisorders of a patient are disclosed where the disorders arecharacterized at least in part by vagal activity innervating at leastone of a plurality of organs of the patient at an innervation site. Themethod includes positioning an electrode on a vagus nerve. An electricalsignal is applied to the electrode to modulate vagal activity by anamount selected to treat the disorder. In some embodiments, the disorderis bulimia. The signal may be a blocking or a stimulation signal. Insome embodiments, the signal is selected to, at least in part,downregulate neural activity on the vagus nerve.

IV. BRIEF DESCRIPTION OF THE DRAWINGS

FIG. 1 is a schematic representation of a gastric-emptying feedback loopwith a patient-controlled stimulator for stimulating an organ of theloop;

FIG. 2 is a view similar to FIG. 1 with an automatic controllerreplacing the patient-controller of FIG. 1 and with feedback circuits tothe automatic controller schematically represented;

FIG. 3 is a schematic illustration of an alimentary tract (GI tract plusnon-GI organs such as the pancreas and liver) and its relation to vagaland enteric innervation;

FIG. 4 is the view of FIG. 3 showing the application of a pacingelectrode according to an embodiment of the present invention;

FIG. 5 is a schematic representation of pacing system;

FIG. 6 is the view of FIG. 4 showing the application of a nerveconduction block electrode proximal to the pacing electrode;

FIG. 7 is the view of FIG. 6 showing the application of a nerveconduction block electrode distal to the pacing electrode;

FIG. 8 is the view of FIG. 3 showing the application of a nerveconduction block electrode according to an embodiment of the presentinvention;

FIG. 9 is a schematic representation of a patients' stomach shownpartially in section and illustrating a representative placement ofanterior and posterior vagus nerves with respect to the anatomy of thestomach and diaphragm;

FIG. 10 is the view of FIG. 9 showing a further embodiment of thepresent invention in utilizing electrode bands;

FIG. 11 is a perspective view of a band for use in the embodiment ofFIG. 10;

FIG. 12 is a side sectional view of a patients' stomach in illustratinga yet alternative embodiment of the present invention;

FIG. 13 is a side elevation view of a balloon portion of an apparatusfor use in the embodiment of FIG. 12;

FIG. 14 is a side elevation view of an alternative embodiment of aballoon portion of an apparatus for use in the embodiment of FIG. 12;

FIG. 15 is a side sectional view of a patients' stomach in illustratinga yet alternative embodiment of the invention of FIG. 12;

FIG. 16 is a side sectional view of a patients' stomach in illustratinga still further alternative embodiment of the invention of FIG. 12;

FIG. 17 is a schematic view of a balloon with magnetic coils;

FIG. 18 is a side sectional view of the esophagus and stomach junctionand illustrating a yet further embodiment of the present invention; and

FIG. 19 is a view similar to that of FIG. 15 and illustrating analternative embodiment of the invention shown in FIG. 15.

V. DESCRIPTION OF THE PREFERRED EMBODIMENT

With reference now to the various drawing figures in which identicalelements are numbered identically throughout, a description of thepreferred embodiment of the present invention will now be described.

A. Invention of Parent Application

FIGS. 1 and 2 and the description which follow are from theaforementioned U.S. patent application Ser. No. 10/358,093 filed Feb. 3,2003 and entitled “Method and Apparatus for Treatment ofGastroesophageal Disease (GERD)”.

With initial reference to FIG. 1, a gastric emptying feedback loop isshown schematically for ease of illustration. The feedback loopillustrates a patient's stomach S which is provided with food from theesophagus E. A lower esophageal sphincter LES is shown positionedbetween the esophagus E and the stomach S. The lower esophagealsphincter normally provides control of reflux of stomach contents intothe esophagus E.

On a proximal or lower end of the stomach S the stomach discharges intothe superior duodenum D which is an upper portion of the intestines. Thesuperior duodenum D and the stomach S are separated by a pyloric valvePV which opens to permit gastric emptying from the stomach into theduodenum D.

Also schematically illustrated in FIG. 1 are nerve paths N providingsignal flow paths from both the superior duodenum D and the stomach S tothe brain B. An efferent Vagal nerve VN connects the brain B to thepancreas P of the patient. A conduit (pancreatic duct PD) extends fromthe pancreas P and discharges into the superior duodenum D.

The presence of food contents within the duodenum D (such contents beingreferred to as “chyme”) may prevent passage of gastric content of thestomach S past the pyloric valve PV into the duodenum D. As long as suchgastric contents cannot be passed into the duodenum D, such contents canbe forced retrograde past the lower esophageal sphincter LES and intothe esophagus E creating the symptoms and discomfort of GERD. Thecontents discharging from the stomach S into the duodenum D are acidic(and high osmolality) and reside in the duodenum D until pH is elevated(close to a neutral pH of 6-7) and osmolality is normalized.

The elevation of pH and reduction of osmolality of chyme in the duodenumD results from exocrine secretion being administered from the pancreas Pand from bile from the liver into the duodenum D. This raises the pH andlowers the osmolality of the duodenum D content permitting dischargefrom the duodenum D and thereby permitting gastric emptying across thepyloric valve PV.

According to the present invention gastroesophageal reflux disease(GERD) results from a derangement of the feedback loops involved inupper GI digestion and motility control. This problem encompassesreceptors and reflexes that regulate the propulsive contractions of thestomach, upper duodenum and biliary tree and the secretions of theexocrine pancreas. The interaction of these receptors and reflexescontrol gastric emptying (by coordinating gastric propulsivecontractions and sphincter [primarily pyloric] tone) and regulate the pHand osmolality of the chyme in the duodenum. This chemo-regulation ismediated through control of bile delivery and stimulation of secretionby the exocrine pancreas of fluid delivered to the superior duodenum.Chey et al., “Neural Hormonal Regulation of Exocrine PancreaticSecretion”, Pancreatology, pp. 320-335 (2001).

Normally, ingestate delivered to the stomach is mixed by low intensitygastric mixing contractions with the enzymatic, ionic, includinghydrogen ion (H+), and water secretions of the glands of the stomach.When the material is adequately reduced in size and is a smoothconsistency, the fluid, now called chyme, is delivered to the ampulla ofthe small intestine by the much stronger propulsive, or emptying,contractions of the stomach coupled with transitory relaxation of thepyloric sphincter. This material is at a very low pH (about 2) and highosmolality, which activates receptors, including those for H⁺ andosmotic pressure, which are abundant in the wall of the ampulla. Thisreceptor activation initiates the series of reflexes that causepancreatic exocrine secretion to be delivered into the superior duodenumand ampulla. This fluid contains digestive enzymes, water and bufferingcompounds to raise the pH, and reduce the osmolality, of the chyme.

Once a neutral pH and physiological osmolality are achieved, thenpropulsive contractions in the superior duodenum move the chyme out ofthe superior portion into the length of the duodenum; at which point thestretch and baro-receptors in the ampulla allow the pyloric sphincter torelax and another bolus of gastric contents is delivered into theampulla by the peristaltic gastric emptying contractions. This material,at a very low pH (less than 2), activates hydrogen ion (H⁺) on receptorsof the ampulla (upper most portion of the duodenum) causing thepancreatic fluids to be delivered to the material in the ampullarestarting the cycle as described above. Chapter 3, “The Stomach”,Gastrointestinal System, 2^(nd) Ed., M. S. Long editor, Mosby Publisher,London (2002).

If the control system is down regulated by, for example, by increased pHof gastric contents entering the ampulla, feedback may thereby bereduced from the H⁺ receptors in the duodenum that stimulate pancreaticexocrine secretion and bile delivery to the duodenum, then movement ofchyme from the superior duodenum is delayed, causing delay of gastricemptying. Mabayo, et al., “Inhibition of Food Passage by Osmeprazole inthe Chicken”, European J. of Pharmacology, pp. 161-165 (1995).

In GERD, this reflex is inhibited in such a way that the stomach emptiesmore slowly so that the gastric emptying contractions force gastriccontents to flow retrograde into the esophagus. This is a result of thesituation in which the gastric emptying contractions are vigorous butmust operate against a contracted pyloric sphincter. These vigorousperistaltic contractions eventually begin to force gastric contents toflow retrograde into the esophagus because of the inherent imbalancebetween a very strong pyloric sphincter and a much weakergastroesophageal sphincter. The delay in gastric emptying is directlyrelated to a slow down in the transport of chyme out of the ampulla andsuperior duodenum. The drugs used to treat this disease raise pH furtherdampening the hydrogen-receptor-pancreatic secretion loop, furtherdelaying gastric emptying. Benini, “Gastric Emptying and DyspepticSymptoms in Patients with Gastroesophageal Reflux”, Amer. J. ofGastroenterology, pp. 1351-1354 (1996).

The present invention is directed towards reestablishing the linkbetween gastric emptying and pancreatic secretion delivery, therebyaddressing the main pathology of this disease by shortening chymeresidence time in the superior duodenum so that intestinal contents moveinto the distal digestive tract in a more normal manner. According to afirst embodiment, this is done by stimulating the H+ ion receptors or bystimulation of the pancreas directly or via its para-sympatheticinnervation (pre-ganglionic Vagal nerves). Stimulation of pancreaticexocrine secretion has been shown by direct stimulation of the thoracicvagus nerves in dogs. Kaminski et al., “The Effect of Electrical VagalStimulation on Canine Pancreatic Exocrine Function”, Surgery, pp.545-552 (1975). This results in a more rapid (normal) neutralization ofchyme in the ampulla, allowing it move down the duodenum more quickly sothat gastric emptying is returned to a more normal pace.

Acidity (pH) can be assessed by measuring bicarbonate. It will beunderstood that references to —H includes such indirect measurements.Also, effects of the therapy described herein can be assessed and/orcontrolled by measuring an indication of pancreatic exocrine secretionor bile (e.g., HCO₃ ⁻).

An alternative embodiment uses gastrocopic delivery of a paralyzingagent (e.g. botulism toxin) to the pyloric valve along with use of H2antagonists or PPI's to manage the acidity of the chyme reaching theduodenum.

As an additional alternative to pancreatic stimulation, the gall bladdercan be stimulated to encourage bile movement into the duodenum. Shownschematically in the figures, the gall bladder GB resides below theliver L. The gall bladder is connected to the small intestine(specifically the duodenum D) via a bile duct BD. The bile duct BD candischarge directly into the duodenum D or via the pancreatic duct PD asshown. The bile can normalize the chyme to accelerate duodenal emptying.Bile consists of bile acids (detergents that emulsify lipids),cholesterol, phospholipids, electrolytes such as (Na⁺, K⁺, Ca⁺², Cl⁻,HCO₃ ⁻) and H₂O. Chapter 4, “The Liver and Biliary Tract”,Gastrointestinal System, 2^(nd) Ed., M. S. Long editor, Mosby Publisher,London (2002). The gall bladder GB or bile duct can be stimulatedindirectly via stimulation of the vagal nerve VN or directly stimulatedby an electrode 11 (shown in phantom lines).

As illustrated in the figures, an electrical stimulator 10, 20 which maybe implanted is provided which alternatively may be directly connectedto the Vagal nerve VN or the pancreas P to stimulate the pancreasdirectly or indirectly to excrete exocrine into the duodenum D (or moredistally into the small intestine—e.g., into the jejunum) and increasethe pH of chyme in the duodenum D as described. Alternatively, the samecan be done to promote bile release. The frequency may be varied tomaximize the response and selectively stimulate exocrine instead ofendocrine secretions. Rösch et al., “Frequency-Dependent Secretion ofPancreatic Amylase, Lipase, Trypsin, and Chymotrypsin During VagalStimulation in Rats”, Pancreas, pp. 499-506 (1990). See, also, Berthoudet al., “Characteristics of Gastric and Pancreatic Reponses to VagalStimulation with Varied Frequencies: Evidence for Different FiberCalibers?”, J. Auto. Nervous Sys., pp. 77-84 (1987) (showedfrequency-response relationship with insulin, i.e., significantly lessinsulin was released at lower frequencies—2 Hz v. 8 Hz—also,frequency-response curves evidenced distinctly different profiles forgastric, pancreatic and cardiovascular responses.) Slight insulinrelease can maximize pancreatic exocrine secretion. Chey et al., “NeuralHormonal Regulation of Exocrine Pancreatic Secretion”, Pancreatology,pp. 320-335 (2001).

With a patient control stimulation as shown in FIG. 1, the patient mayactivate the stimulator 10 by remote transmitter to stimulate anelectrical charge either after eating (e.g., about 60 to 90 minutesafter eating) or on onset of GERD symptoms. It will be appreciated thatthere are a wide variety of nerve stimulators and organ stimulatorsavailable for implantation and are commercially available and whichinclude connectors for connecting directly to nerves.

FIG. 2 illustrates an additional embodiment where the patient activatedloop is replaced with an automatic loop having a programmable stimulator20 which receives as an input signals from sensors in the duodenum tomeasure pH, osmolality or strain (e.g., from baro-sensors) on theduodenum indicating filling or may measure acidity in the esophagus orstrain on the lower esophageal sphincter LES or stomach S all of whichmay be provided to the implantable controller 20 which can be providedwith desirable software to process the incoming signals and generate astimulating signal to either the vagal nerve, the pancreas P or theduodenum D (or jejunum) directly in response to such received signals.It will be appreciated that stimulators and controllers are well withinthe skill of the art. U.S. Pat. No. 5,540,730 teaches a neurostimulatorto stimulate a vagus nerve to treat a motility disorder. U.S. Pat. No.5,292,344 teaches gastrointestinal sensors, including pH sensors.

B. Application of Parent Application to Treatments Other than GERD

In addition to treatment of GERD, the foregoing invention is applicableto treatment of a plurality of GI diseases associated with delayedgastric emptying or altered autonomic activity. These include functionalgastrointestinal disorders and gastroparesis. Furthermore, applicantshave determined that duodenal content impacts a plurality of motilitydisorders throughout the bowels and can diseases associated withdysmotility (e.g., irritable bowel syndrome). Accordingly it is anobject of the present invention to use the teachings of theaforementioned parent application to treat GI disorders associated withdelayed gastric emptying and abnormal intestinal transport.

C. Additional Disclosure of the Present Application

1. Enteric Innervation

FIG. 3 is a schematic illustration of an alimentary tract (GI tract plusnon-GI organs such as the pancreas and ball bladder, collectivelylabeled PG) and its relation to vagal and enteric innervation. The loweresophageal sphincter (LES) acts as a gate to pass food into the stomachS and, assuming adequate function of all components, prevent reflux. Thepylorus PV controls passage of chyme from the stomach S into theintestines I (collectively shown in the figures and including the largeintestine or colon and the small intestine including the duodenum,jejunum and ileum).

The biochemistry of the contents of the intestines I is influenced bythe pancreas P and gall bladder PG which discharge into the duodenum.This discharge is illustrated by dotted arrow A.

The vagus nerve VN transmits signals to the stomach S, pylorus PV,pancreas and gall bladder PG directly. Originating in the brain, thereis a common vagus nerve VN in the region of the diaphragm (not shown).In the region of the diaphragm, the vagus VN separates into anterior andposterior components with both acting to innervate the GI tract. InFIGS. 3, 5-8, the anterior and posterior vagus nerves are not shownseparately. Instead, the vagus nerve VN is shown schematically toinclude both anterior and posterior nerves.

The vagus nerve VN contains both afferent and efferent componentssending signals away from and to, respectively, its innervated organs.

In addition to influence from the vagus nerve VN, the GI and alimentarytracts are greatly influenced by the enteric nervous system ENS. Theenteric nervous system ENS is an interconnected network of nerves,receptors and actuators throughout the GI tract. There are many millionsof nerve endings of the enteric nervous system ENS in the tissues of theGI organs. For ease of illustration, the enteric nervous system ENS isillustrated as a line enveloping the organs innervated by the entericnervous system ENS.

The vagus nerve VN innervates, at least in part, the enteric nervoussystem ENS (schematically illustrated by vagal trunk VN3 whichrepresents many vagus-ENS innervation throughout the cut). Also,receptors in the intestines I connect to the enteric nervous system ENS.Arrow B in the figures illustrates the influence of duodenal contents onthe enteric nervous system ENS as a feedback to the secretion functionof the pancreas, liver and gall bladder. Specifically, receptors in theintestine I respond the biochemistry of the intestine contents (whichare chemically modulated by the pancreao-biliary output of Arrow A).This biochemistry includes pH and osmolality.

In the figures, vagal trunks VN1, VN2, VN4 and VN6 illustrateschematically the direct vagal innervation of the GI organs of the LES,stomach S, pylorus PV and intestines I. Trunk VN3 illustrates directcommunication between the vagus VN and the ENS. Trunk VN5 illustratesdirect vagal innervation of the pancreas and gall bladder. Entericnerves ENS1-ENS4 represent the multitude of enteric nerves in thestomach S, pylorus PV, pancreas and gall bladder PG and intestines I.

While communicating with the vagus nerve VN, the enteric nervous systemENS can act independently of the vagus and the central nervous system.For example, in patients with a severed vagus nerve (vagotomy—anhistorical procedure for treating ulcers), the enteric nervous systemcan operate the gut. Most enteric nerve cells are not directlyinnervated by the vagus. Gershon, “The Second Brain”, Harper CollinsPublishers, Inc, New York, N.Y. p. 19 (1998).

In FIG. 3, the vagus VN and its trunks (illustrated as VN1-VN6) and theenteric nervous system ENS are shown in phantom lines to illustratereduced vagal and enteric nerve tone (i.e., sub-optimal nervetransmission levels). Reduced vagal and enteric tone contribute directlyto the ineffectiveness of the GI organs as well as indirectly (throughreduced pancreatic/biliary output). The reduced pancreatic/biliaryoutput is illustrated by the dotted presentation of arrow A. Aspreviously discussed, the vagus can be stimulated to stimulatepancreatic or biliary output. Therefore, the reduced output of arrow Aresults in a reduced feedback illustrated by the dotted presentation ofarrow B.

2. Enteric Rhythm Management (ERM)

The benefits of the present invention are illustrated in FIG. 4 where astimulating or pacing electrode PE is applied to the vagus VN. Whileonly one electrode is shown in FIG. 4, separate electrodes could beapplied to both the anterior and posterior vagus nerves (or to thecommon vagus or vagal branches). In a preferred embodiment, theelectrode PE is placed a few centimeters below the diaphragm andproximal to stomach and pancreo/biliary innervation. While thisplacement is presently preferred for ease of surgical access, otherplacement locations may be used.

By pacing the vagus through the pacing electrode, vagal tone isoptimized by either up- or down-regulation. With reference to theparasympathetic and enteric nervous systems, “tone” refers to basalactivity of a nerve or nervous system facilitating appropriatephysiologic response to a patient's internal environment. For example,low vagal tone implies a reduction in vagus nerve activity resulting indecreased response of the alimentary tract to ingested food. As used inthe present application, “pacing” is not limited to mean timed eventscoordinated with specifically timed physiologic events. Instead, pacingmeans any electrical stimulation of a nerve trunk to inducebi-directional propagation of nervous impulses in the stimulated nerve.

The operating effectiveness of the vagus is enhanced so that localphysiological signals generated in the enteric nervous system (or sentto the brain from the organs) are more appropriately responded to withinthe alimentary tract. Due to its innervation of the enteric nervoussystem, pacing of the vagus enhances the functional tone of the entericnervous system. By enhancing the functional tone it will be noted thatthe stimulation pacing is elevating the degree of functionality of thevagus and enteric nerves. In this context, “pacing” is not meant to meantimed pulsed coordinated with muscular contractions or synchronized withother invents. Pacing means elevating the activity level of the nerves.

Tonal enhancement of the vagus and enteric nerves is illustrated by thesolid lines for the nerves VN, ENS in FIG. 4. Vagal trunk VN5 is insolid line to illustrate enhanced tone of the many vagal nervecomponents communicating with the enteric nervous system ENS. Directvagal innervation of the LES, stomach S, pylorus PV and intestines Iremains shown as low tone indicated by phantom lines VN1, VN2, VN4, VN6.The tonal pacing described herein is not intended to trigger or drivethe muscular contractility of these organs. The stimulation is notintended to be timed to trigger contractility and is not provided withan energy level sufficient to drive peristaltic contractions. Instead,these functions remain controlled by the central and enteric nervessystems. The enhanced nerve tone provided by the present inventionpermits these functions to occur.

Pacing to enhance vagal tone is not initiated in response to any sensesevent (or in anticipation of an immediate need to GI activity). Instead,the pacing can be done intermittently over the day to provide anenhanced level of operating functionality to the vagus. By way ofnon-limiting example, the stimulation pacing can be done during awakehours. For example, every ten minutes, pacing signals can be sent to thepacing electrodes. The pacing signals have a duration of 30 seconds witha current of 4 mA, a frequency of 12 Hz and an impulse duration of 2msec. These parameters are representative only. A wide range of signalparameters may be used to stimulate the vagus nerve. Examples of theseare recited in the afore-referenced literature.

As will be further discussed, the present invention permits ERM to beuniquely designed and modified by an attending physician to meet thespecific needs of individual patients. For example, pacing can belimited to discrete intervals in the morning, afternoon and evening withthe patient free to coordinate meals around these events.

In addition to enhancing vagal and enteric tone directly, the pacingalso enhances the pancreatic and biliary output for the reasonsdiscussed above. Namely, while ERM does not drive muscular events overnerve trunks VN1, VN2, VN4, VN6, the enhanced tone stimulatespancreo-biliary output over trunk VN5 (illustrated by the solid line ofVN5 in FIG. 4). This enhanced output is illustrated as solid arrow A′ inFIG. 4. As a consequence there is a greater feedback to the intestinalreceptors as illustrated by solid arrow B′ in FIG. 4. This enhancedbiochemistry feedback further enhances the tone of the enteric nervoussystem ENS.

3. Implantable Pacing Circuit

A representative pacing circuit 100 is schematically shown in FIG. 5.Similar to cardiac pacing devices, an implantable controller 102contains an induction coil 104 for inductive electrical coupling to acoil 106 of an external controller 108. The implantable controller 102includes anterior and posterior pulse generators 110, 112 electricallyconnected through conductors 114, 116 to anterior and posterior pacingelectrodes 118, 120 for attachment to anterior and posterior trunks,respectively, of the vagus nerve VN. The implantable controller 102 alsoincludes a battery 122 and a CPU 124 which includes program storage andmemory. The timing and parameters of the pulse at the electrodes 118,120 can be adjusted by inductively coupling the external controller 108to the implantable controller 102 and inputting pacing parameters (e.g.,pulse width, frequency and amplitude).

While a fully implantable controller 102 is desirable, it is notnecessary. For example, the electrodes 118, 120 can be implantedconnected to a receiving antenna placed near the body surface. Thecontrol circuits (i.e., the elements 124, 110, 112 and 108) can behoused in an external pack worn by the patient with a transmittingantenna held in place on the skin over the area of the implantedreceiving antenna. Such a design is forward-compatible in that theimplanted electrodes can be later substituted with the implantablecontroller 102 at a later surgery if desired.

Although not shown in FIG. 5, the controller 102 can also includecircuits generating nerve conduction block signals (as will bedescribed) which connect to electrodes which may be positioned on anerve proximally, distally (or both) of the electrodes 118, 120.

4. Nerve Conduction Block

FIG. 6 shows an alternative embodiment using a nerve conduction blockingelectrode PBE proximal to the pacing electrode for providing aconduction block. A nerve block is, functionally speaking, a reversiblevagotomy. Namely, application of the block at least partially preventsnerve transmission across the site of the block. Removal of the blockrestores normal nerve activity at the site. A block is any localizedimposition of conditions that at least partially diminish transmissionof impulses.

The vagal block may be desirable in some patients since unblocked pacingmay result in afferent vagal and antidromic efferent signals havingundesired effect on organs innervated by the vagus proximal to the GItract (e.g., undesirable cardiac response). Further, the afferentsignals of the pacing electrode PE can result in a central nervoussystem response that tends to offset the benefits of the pacingelectrode on the ENS and pancreo/biliary function, thereby reducing theGI and enteric rhythm management effectiveness of vagal pacing.

The block may be intermittent and applied only when the vagus is pacedby the pacing electrode PE. The preferred nerve conduction block is anelectronic block created by a signal at the vagus by an electrode PBEcontrolled by the implantable controller (such as controller 102 or anexternal controller). The nerve conduction block can be any reversibleblock. For example, cryogenics (either chemically or electronicallyinduced) or drug blocks can be used. An electronic cryogenic block maybe a Peltier solid-state device which cools in response to a current andmay be electrically controlled to regulate cooling. Drug blocks mayinclude a pump-controlled subcutaneous drug delivery.

With such an electrode conduction block, the block parameters (signaltype and timing) can be altered by a controller and can be coordinatedwith the pacing signals to block only during pacing. A representativeblocking signal is a 500 Hz signal with other parameters (e.g., timingand current) matched to be the same as the pacing signal). While analternating current blocking signal is described, a direct current(e.g., −70 mV DC) could be used. The foregoing specific examples ofblocking signals are representative only. Other examples and ranges ofblocking signals are described in the afore-mentioned literature (allincorporated herein by reference). As will be more fully described, thepresent invention gives a physician great latitude in selected pacingand blocking parameters for individual patients.

Similar to FIG. 4, the vagus VN and enteric nervous system ENS in FIG. 6distal to the block PBE are shown in solid lines to illustrate enhancedtone (except for the direct innervation VN1, VN2, VN4, VN6 to the GItract organs). Similarly, arrows A′, B′ are shown in solid lines toillustrate the enhanced pancreo-biliary output and resultant enhancedfeedback stimulation to the enteric nervous system ENS. The proximalvagus nerve segment VNP proximal to the block PBE is shown in phantomlines to illustrate it is not stimulated by the pacing electrode PEwhile the blocking electrode PBE is activated.

5. Proximal and Distal Blocking

FIG. 7 illustrates the addition over FIG. 6 of a nerve conductive blockDBE distal to the pacing electrode PE. The proximal block PBE preventsadverse events resulting from afferent signals and heightens the GIeffectiveness by blocking antidromic interference as discussed withreference to FIG. 6.

In FIG. 7, the distal block DBE is provided in the event there is adesire to isolate the pacing effect of electrode PE. For example, aphysician may which to enhance the vagus and enteric activity in theregion proximal to the duodenum but may wish to avoid stimulatingpancreo-biliary output. For example, a patient may have a GI problemwithout apparent colon dysfunction (e.g., gastroparesis functionaldyspepsia without bowel symptoms). Placing the distal block DBE on abranch of the vagus between the pacing electrode PE and the pancreas andgall bladder PG prevents increased pancreo-biliary output and resultantfeedback (illustrated by dotted arrows A and B in FIG. 7 and dotteddistal vagal nerve segment VND and vagal trunk VN5).

6. Blocking as an Independent Therapy

FIG. 8 illustrates an alternative embodiment of the invention.

In certain patients, the vagus nerve may be hyperactive contributing todiarrhea-dominant IBS. Use of a blocking electrode alone in the vaguspermits down-regulating the vagus nerve VN, the enteric nervous systemENS and pancreo-biliary output. The block down-regulates efferent signaltransmission. In FIG. 8, the hyperactive vagus is illustrated by thesolid line of the proximal vagus nerve segment VNP. The remainder of thevagus and enteric nervous system are shown in reduced thickness toillustrate down-regulation of tone. The pancreo-biliary output (andresulting feedback) is also reduced. In FIG. 8, the blocking electrodeBE is shown high on the vagus relative to the GI tract innervation(e.g., just below the diaphragm), the sole blocking electrode could beplaced lower (e.g., just proximal to pancreo/biliary innervation VN5).

The use of blocking as an independent therapy also permits treatment forpancreatitis by down regulating vagal activity and pancreatic outputincluding pancreatic exocrine secretion. Also, the blocking may be usedas a separate treatment for reducing discomfort and pain associated withgastrointestinal disorders or other vagally mediated pain (i.e., somaticpain sensations transmitted along any nerve fibers with pain sensationmodulated by vagal afferent fibers). A nerve stimulation to treat painis described in U.S. patent application publication No. US2003/0144709to Zabara et al., published Jul. 31, 2003.

It will be appreciated that patient discomfort and pain is a primarycomplaint associated with many gastrointestinal disorders. As used inthe present application (and appended claims), it will be appreciatedthat a treatment of a gastrointestinal disorder may include a treatmentof a patient's perception of pain without any additional functionaltherapy associated with a gastrointestinal disorder. Vagal blocking asdescribed herein can treat gastrointestinal pain or discomfort(including that associated with Crohn's disease) and chronic somaticpain as well as the inflammatory basis of Crohn's disease. The vagalblocking as described herein can also treat nausea secondary, forexample, to chronic cancer chemotherapy.

7. Application to Obesity

The foregoing discussion has been described in a preferred embodiment oftreating FGIDs, gastroparesis and GERD. Obesity is also treatable withthe present invention.

Recent literature describes potential obesity treatments relative to guthormone fragment peptide YY₃₋₃₆. See, e.g., Batterham, et al.,“Inhibition of Food Intake in Obese Subjects by Peptide YY3-36”, NewEngland J. Med., pp. 941-948 (Sep. 4, 2003) and Korner et al., “To Eator Not to Eat—How the Gut Talks to the Brain”, New England J. Med., pp.926-928 (Sep. 4, 2003). The peptide YY₃₋₃₆(PPY) has the effect ofinhibiting gut motility through the phenomena of the ileal brake. Vagalafferents create a sensation of satiety.

The present invention can electrically simulate the effects of PPY byusing the vagal block to down-regulate afferent vagal activity to createa desired sensation of satiety. Since the down-regulation does notrequire continuous blocking signals, the beneficial efferent signals arepermitted.

8. Application to Other Therapies

There are numerous suggestions for vagal pacing or stimulation to treata wide variety of diseases. For example, U.S. Pat. No. 5,188,104 datedFeb. 23, 1993 describes vagal stimulation to treat eating disorders.U.S. Pat. No. 5,231,988 dated Aug. 3, 1993 describes vagal stimulationto treat endocrine disorders. U.S. Pat. No. 5,215,086 dated Jun. 1, 1993describes vagal stimulation to treat migraines. U.S. Pat. No. 5,269,303dated Dec. 14, 1993 describes vagal stimulation to treat dementia. U.S.Pat. No. 5,330,515 dated Jul. 19, 1994 describes vagal stimulation totreat pain. U.S. Pat. No. 5,299,569 dated Apr. 5, 1994 describes vagalstimulation to treat neuropsychiatric disorders. U.S. Pat. No. 5,335,657dated Aug. 9, 1994 describes vagal stimulation to treat sleep disorders.U.S. Pat. No. 5,707,400 dated Jan. 13, 1998 describes vagal stimulationto treat refractory hypertension. U.S. Pat. No. 6,473,644 dated Oct. 29,2002 describes vagal stimulation to treat heart failure. U.S. Pat. No.5,571,150 dated Nov. 5, 1996 describes vagal stimulation to treatpatients in comas. As previously described, U.S. Pat. No. 5,540,730dated Jul. 30, 1996 describes vagal stimulation to treat motilitydisorders and U.S. Pat. No. 6,610,713 dated Aug. 26, 2003 describesvagal stimulation to inhibit inflammatory cytokine production. All ofthe foregoing U.S. patents listed in this paragraph are incorporatedherein by reference.

All of the foregoing suffer from undesired effects of vagal pacing oncardiovascular, gastrointestinal or other organs. Nerve conductionblocking permits longer pulse durations which would otherwise haveadverse effects on other organs such as those of the cardiovascular orgastrointestinal systems. In accordance with the present invention, allof the foregoing disclosures can be modified by applying a blockingelectrode and blocking signal as disclosed herein to prevent adverseside effects. By way of specific example, pacing a vagus nerve in thethoracic cavity or neck combined with a blocking electrode on the vagusnerve distal to the pacing electrode can be used to treatneuropsychiatric disorders (such as depression and schizophrenia) andParkinson's and epilepsy and dementia. In such treatments, the blockingelectrode is placed distal to the stimulating electrode 25 shown inFIGS. 4 and 2, respectively, of each of U.S. Pat. Nos. 5,269,303 and5,299,569. The present invention thereby enables the teachings of theafore-referenced patents listed in foregoing two paragraphs.

As described, the parameters of the stimulating and blocking electrodescan be inputted via a controller and, thereby, modified by a physician.Also, FIG. 2 illustrates a feedback for controlling a stimulatingelectrode. Feedbacks for stimulating electrodes are also described inthe patents incorporated by reference. The blocking electrode can alsobe controlled by an implanted controller and feedback system. Forexample, physiologic parameters (e.g., heart rate, blood pressure, etc.)can be monitored. The blocking signal can be regulated by the controllerto maintain measured parameters in a desired range. For example,blocking can be increased to maintain heart rate within a desired raterange during stimulation pacing.

9. Opportunity for Physician to Alter Treatment for Specific Patient

Gastrointestinal disorders are complex. For many, the precise mechanismof the disorder is unknown. Diagnosis and treatment are often iterativeprocesses. The present invention is particularly desirable for treatingsuch disorders.

Use of proximal and distal blocking electrodes in combination with oneor more pacing electrode permits a physician to alter an operatingpermutation of the electrodes. This permits regional and local up- ordown-regulation of the nervous system and organs. Further, pacingparameters (duty cycle, current, frequency, pulse length) can all beadjusted. Therefore, the treating physician has numerous options toalter a treatment to meet the needs of a specific patient.

In addition, a physician can combine the present invention with othertherapies (such as drug therapies like prokinetic agents).

D. Alternative Embodiments

1. Background

With reference to FIG. 9, a stomach S is shown schematically for thepurpose of facilitating an understanding of alternative embodiments ofthe invention as illustrated in FIGS. 10-15. In FIG. 9, the stomach S isshown with a collapsed fundus F which is deflated due to fasting. Inpractice, the fundus F can be reduced in size and volume (as shown inFIG. 9) or expanded (as shown in FIG. 12).

The esophagus E passes through the diaphragm D at an opening or hiatusH. In the region where the esophagus E passes through the diaphragm D,trunks of the vagal nerve (illustrated as the anterior vagus nerve AVNand posterior vagus nerve PVN) are disposed on opposite sides of theesophagus E. It will be appreciated that the precise location of theanterior and posterior vagus nerves AVN, PVN relative to one another andto the esophagus E are subject to a wide degree of variation within apatient population. However, for most patients, the anterior andposterior vagus nerves AVN, PVN are in close proximity to the esophagusE at the hiatus H where the esophagus E passes through the diaphragm D.

The anterior and posterior vagus nerves AVN, PVN divide into a pluralityof trunks that innervate the stomach directly and via the entericnervous system and may include portions of the nerves which may proceedto other organs such as the pancreas, gallbladder and intestines.Commonly, the anterior and posterior vagus nerves AVN, PVN are still inclose proximity to the esophagus E and stomach (and not yet extensivelybranched out) at the region of the junction of the esophagus E andstomach S.

In the region of the hiatus H, there is a transition from esophagealtissue to gastric tissue. This region is referred to as the Z-line(labeled “Z” in the Figures). Above the Z-line, the tissue of theesophagus is thin and fragile. Below the Z-line, the tissue of theesophagus E and stomach S are substantially thickened and more vascular.Within a patient population, the Z-line is in the general region of thelower esophageal sphincter. This location may be slightly above,slightly below or at the location of the hiatus H.

2. Implanted Band Electrode

a. Description of Device

With reference to FIG. 10, a band 200 is shown placed around theesophagus E below the diaphragm D and overlying the anterior andposterior vagus nerves AVN, PVN at the cardiac notch CN. Alternatively,it can be placed completely around the upper portion of the stomach nearits junction of the esophagus. Placement of a band 200 around theesophagus E directly beneath the diaphragm D ensures that the band maybe placed around the anterior and posterior vagus nerves AVN, PVNwithout the need for extensive dissection of the nerves AVN, PVN.

The band 200 may be formed of polyester or the like or any othersuitable material which may be sutured in place or otherwise fastened inplace surrounding the esophagus E or gastric cardia. Preferably, theband 200 is placed at the junction of the esophagus E and stomach S suchthat the band may overly both the esophagus E and stomach S at thecardiac notch CN.

The band 200 may have a plurality of electrodes which, in the embodimentof FIG. 10 include an upper electrode array 202 and a lower electrodearray 203. In the embodiment of FIG. 11 (in which a band 200 is shownlying flat), the electrode arrays 202, 203 are shown with electrodesplaced at an angle relative to the cylindrical axis X-X of the band 200.

Placement of the band 200 as described ensures that at least a subset ofthe electrodes 202, 203 will be in overlying relation to the anteriorand posterior vagus nerves AVN, PVN. As a result, energizing theelectrodes 202, 203 will result in stimulation of the anterior andposterior vagus nerves AVN, PVN and/or their branches.

In therapeutic applications, the upper array 202 of electrodes may beconnected to a blocking electrical signal source (with a blockingfrequency and other parameters as previously described) and the lowerarray 203 of electrodes may be connected to a stimulation electricalsignal source as previously described. Of course, only a single array ofelectrodes could be used with all electrodes connected to either ablocking or a stimulating signal.

The electrical connection of the electrodes 202, 203 to a controller isnot shown but may be as previously described by having a leadsconnecting the electrodes directly to an implantable controller.Alternatively, and as previously described, electrodes may be connectedto an implanted antenna for receiving a signal to energize theelectrodes.

The use of an array of electrodes permits the collar 200 to be placedwithout the need for great accuracy at the time of placement. In theevent it is desirable that electrodes not directly overlying a vagusnerve be deactivated, the electrodes could, through operation of acontroller, be individually energized to detect a physiologicalresponse. The absence of a physiological response (other than possiblemuscular action of the stomach and esophagus) would indicate the absenceof an overlying relation to a vagus nerve. The presence of aphysiological response would indicate overlying relation of the testedelectrode to a vagus nerve.

By identifying which electrodes create a physiologic response, theremaining electrodes (i.e., those not having a physiological response)could be permanently deactivated. An example of a physiological responsewould be a cardiovascular response which may be attributed to a signalof about 2-80 hertz and up to 50 milliamps and as more fully describedin U.S. Pat. No. 6,532,388 to Hill et al dated Mar. 11, 2003. As aresult, a selected one of the AVN or PVN could be energized.

It will be appreciated the foregoing description of identifyingelectrodes to be deactivated is a non-limiting embodiment. For example,all electrodes could be energized. The therapies as previously describedcould be employed by using blocking electrodes or stimulation electrodesor both in order to block or energize (or both) the vagus nerve.

FIG. 10 also illustrates an alternative embodiment in the form of a band200′ surrounding the body of the stomach S and having arrays 202′, 203′.Since the band 200′ is more distal to the esophagus E, different andmore distal trunks of the vagus nerves would be energized. Also, such aplacement would permit the option of covering the anterior vagus nervewhile not covering the posterior vagus nerve (or visa versa).

With the embodiment shown in FIG. 10, the benefits of vagal stimulationwith resulting enteric rhythm management and the aforementioned benefitsof blocking can be achieved without the need for extensive dissection ofthe vagus nerve. Further, the benefits can be achieved without the needfor directly clamping electrodes on a vagus nerve, thereby reducing thepossibility of injury to a vagus nerve.

In addition to the benefits of nerve stimulation, the band 200 can alsobe used to restrict and potentially lengthen the esophagus therebyreducing possibilities for reflux as more fully described in commonlyassigned and co-pending U.S. patent application Ser. No. 10/600,088filed Jun. 20, 2003 and entitled “Gastro-Esophageal Reflux Disease”(GERD) Treatment Method and Apparatus” (published Dec. 23, 2004 asPublication No. US 2004/0260316 A1).

b. Application to Obesity and Satiety

The embodiment of FIG. 10 is particularly suitable for the treatment ofobesity. Obesity is of epidemic proportions and is associated with largedecreases in life expectancy and early mortality. Peeters, et al.,“Obesity in Adulthood and Its Consequences for Life Expectancy: A LifeTable Analysis”, Annals of Internal Medicine, Vol. 138, No. 1, pp. 24-32(2003).

In the embodiment of FIG. 10, the upper band 200 is placed around thestomach near the cardiac notch CN. Electrode array 202 may bede-activated (or not present on the band 200). Lower array 203 can beenergized with a blocking signal.

The prior art suggests stimulating the vagas with a stimulating signalfor treating obesity or eating disorders. See, e.g., U.S. Pat. No.5,188,104 to Wernicke et al., dated Feb. 23, 1993; U.S. Pat. No.5,263,480 to Wernicke et al., dated Nov. 23, 1993; U.S. Pat. No.6,587,719 to Barrett et al., dated Jul. 1, 2003 and U.S. Pat. No.6,609,025 to Barrett et al., dated Aug. 19, 2003. These patents alldescribe stimulating, non-blocking signals (e.g., stimulating to a levelslightly below a so-called “retching threshold” as described in the '025patent). As such, all fail to note the problem associated with obesityand eating discords that is not addressed by stimulating the vagus but,rather, by blocking stimulation on the vagus.

The blocking at cardiac notch CN reduces fundal accommodation andcreates satiety sensations. Such a physiologic response is suggested byvagotomy data in which truncal vagotomy patients have experienced weightloss and increased satiety. See, e.g., Kral, “Vagotomy as a Treatmentfor Morbid Obesity”, Surg. Clinics of N. Amer., Vol. 59, No. 6, pp.1131-1138 (1979), Gortz, et al., “Truncal Vagotomy Reduces Food andLiquid Intake in Man”, Physiology & Behavior, Vol. 48, pp. 779-781(1990), Smith, et al., “Truncal Vagotomy in Hypothalamic Obesity”, TheLancet, pp. 1330-1331 (1983) and Kral, “Vagotomy for Treatment of SevereObesity”, The Lancet, pp. 307-308 (1978).

The optional lower band 200′ is placed lower on the stomach (e.g., closeto the pylorus). The lower electrode array 203′ of the lower band 200′is energized with a stimulation signal to modulate intestinal motilityin the event motility is otherwise impaired by the upper band blocking.

The upper array 202′ of the lower band 200′ is energized with a blockingsignal so that the stimulation signal at electrodes 203′ does notinterfere with the blocking effect of electrodes 203 of upper band 200.In this obesity treatment, the electrodes of the bands 200, 200′ can beplaced on constricting bands (such as the well-known Lap-Band® system ofInamed Inc., Santa Barbara, Calif., USA, and used in obesity treatment).More preferably, the bands 200, 200′ are not constricting therebyminimizing erosion risks otherwise associated with highly constrictingbands. However, the neural blocking technology of the present inventioncan be incorporated into such constricting bands or used in conjunctionother obesity surgeries or therapies. Specifically, the scientificliterature indicates a vagotomy in combination with other obesityprocedure (e.g., antrectomy, gastroplasty and biliopancreatic bypass)improves weight loss procedures. Tzu-Ming, et al., “Long-Term Results ofDuodenectomy with Highly Selective Vagotomy in the Treatment ofcomplicated Duodenal Ulcers”, Amer. J. of Surg., Vol. 181, pp. 372-376(2001), Kral, et al., “Gastroplasty for Obesity: Long-Term Weight LossImproved by Vagotomy”, World J. Surg., Vol. 17, pp. 75-79 (1993), andBiron, et al., “Clinical Experience with Biliopancreatic Bypass andGastrectomy or Selective Vagotomy for Morbid Obesity”, Canadian J. ofSurg., Vol. 29, No. 6, pp. 408-410 (1986).

Vagal neural blocking simulates a vagotomy but, unlike a vagotomy, isreversible and controllable. Therefore, while obesity is particularlydescribed as a preferred treatment, the vagal neural block of thepresent invention can be used as a less drastic procedure for treatmentspreviously performed with a vagotomy. Without limitation, these includeobesity, ulcers or chronic pain or discomfort (alone or in combinationwith conjunctive procedures).

Further, bulimia has been identified as a disease amenable to treatmentby decreasing afferent vagal activity via pharmacological vagalinhibitors delivered systemically. Faris, et al., “Effect of DecreasingAfferent Vagal Activity with Ondansetron on Symptoms of Bulimia Nervosa:a Randomized, Double-Blind Trial”, The Lancet, pp. 792-797 (2000).Therefore, bulimia and other diseases treatable with vagal blocker drugscan be treated with the targeted and site-specific vagal neural block ofthe present invention.

3. Acute Treatment Device

a. Device Description

FIG. 12 illustrates a still further embodiment of the present inventionwhere a nasogastric tube 300 is passed into the stomach. It will beappreciated that nasogastric tubes are well known and form no part ofthis invention per se. Some nasogastric tubes have specializedfunctions. An example is a tamponade tube having gastric and esophagealballoons. An example of such is the Bard® Minnesota Four LumenEsophagogastric Tamponade Tube for the Control of Bleeding fromEsophageal Varices as described in product literature (information foruse) contained with the product of that name dated 1998 by C. R. Bard,Inc., Covington, Ga., USA. Further, while a nasogastric tube is apreferred embodiment other devices (e.g., an orogastric tube or anyelongated device to position electrodes near the esophagus/stomachjunction) could be used. Also, while placement at the esophagus/stomachjunction is preferred, the device can be placed in a different lumen(e.g., the trachea) for transmucosal stimulation.

The nasogastric tube 300 is multi-lumen tube which includes distalopenings 302 to which suction can be applied to remove gastric contentsthrough the tube 300. A compliant balloon 304 surrounds the gastrictube. Proximal to the balloon 304 is an opening 309 in communicationwith a lumen (not shown) to which a suction can be applied to removesaliva through the opening 309.

The balloon 304 has a plurality of electrodes which may include an upperarray 306 of electrodes and a lower array 307 of stimulation electrodes.The electrodes of the upper array 306 may be connected to a blockingsignal source via conductors 306 a (FIG. 13). The electrodes of thelower array 307 may be connected to a stimulation signal source viaconductors 307 a. The conductors 306 a, 307 a may be passed through alumen in the tube 300 to an external controller (not shown). As aresult, multiple electrodes can be energized for transmucosalstimulation of the anterior and posterior vagus nerves AVN, PVN. FIG. 14shows an alternative design where the arrays 306, 307 are replaced withexpandable, circumferential electrodes 306′, 307′ connected to acontroller (not shown) by conductors 306 a′, 307 a′.

As in the embodiment of FIG. 10, the individual electrodes of the arrays306, 307 may optionally be selectively energized to detect acardiovascular signal indicating an electrical coupling of theelectrodes to the vagus nerves AVN, PVN. Electrodes that do not createsuch a coupling may optionally be deactivated such that only theelectrodes having an effective coupling with the vagus nerves AVN, PVNwill be activated. Also, and as in the embodiment of FIG. 10, there maybe a single array of electrodes or all electrodes may be energized witheither a blocking or stimulation signal.

It will be noted in this embodiment that the electrodes are disposedabutting the mucosal surface of the esophageal and stomach lining andare not in direct contact with the vagus nerves AVN, PVN. Instead, theelectrodes are spaced from the vagus nerves AVN, PVN by the thickness ofthe stomach and lower esophageal wall thickness.

Transmucosal electrical stimulation of nerves is well known. Suchstimulation is disclosed in U.S. Pat. No. 6,532,388 to Hill et al datedMar. 11, 2003 (describing transmucosal stimulation of nerves across atrachea using a balloon with electrodes in the trachea to modulatecardiac activity). Also, the phenomena of transmucosal electricalstimulation of nerves is described in Accarino, et al, “SymptomaticResponses To Stimulation Of Sensory Pathways In The Jejunum”, Am. J.Physiol., Vol. 263, pp. G673-G677 (1992) (describing afferent pathwaysinducing perception selectively activated by transmucosal electricalnerve stimulation without disruption of intrinsic myoelectrical rhythm);Coffin, et al, “Somatic Stimulation Reduces Perception Of Gut DistentionIn Humans”, Gastroenterology, Vol. 107, pp. 1636-1642 (1994); Accarino,et al, “Selective Dysfunction Of Mechano Sensitive Intestinal AfferentsIn Irritable Bowel Syndrome”, Gastroenterology, Vol. 108, pp. 636-643(1994), Accarino, et al “Modification Of Small Bowel MechanosensitivityBy Intestinal Fat”, GUT, Vol. 48, pp. 690-695 (2001); Accarino, et al,“Gut Perception In Humans Is Modulated By Interacting Gut Stimuli”, Am.J. Physiol. Gastrointestinal Liver Physiol., Vol. 282, pp. G220-G225(2002) and Accarino, et al, “Attention And Distraction Colon Affects OnGut Perception”, Gastroenterology, Vol. 113, pp. 415-442 (1997).

Alternative embodiments of the transmucosal stimulation device of FIG.12 are shown in FIGS. 15 and 16. In FIG. 15, the balloon 304′ is conicalin shape with a base end 304 a′ placed distally on the tube 300′. Afterexpansion, the base end 304 a′ expands within the stomach S. Thephysician then pulls on the tube 300′. The base end 304 a′ (which islarger in diameter than the esophagus E) abuts the stomach S at thecardiac notch CN acting as a stop. This insures the electrodes 305′(only a single array is shown for ease of illustration) abuts themucosal tissue at the junction of the stomach S and esophagus E. Theelectrodes 305′ are on the narrow end 304 b′ of the balloon 304′ andexpansion of the balloon 304′ ensures contact of the electrodes with themucosal tissue.

FIG. 16 illustrates an embodiment using two balloons 304″ and 309″. Thedistal balloon 309″, when expanded, is larger than the esophagus E andacts as a stop when the physician pulls on the tube 300″. The electrodes305″ are on a smaller balloon 304″ which may expand in the esophagus E.The balloon 304″, 309″ are positioned for the electrodes 305″ to beagainst the mucosal tissue at the junction of the stomach S andesophagus E when the distal balloon 309″ abuts the cardiac notch CN andthe proximal balloon 304″ is expanded. The electrodes may be positionedto be completely within the stomach to reduce risk of injury toesophageal tissue. More conveniently, a tube such as the afore-mentionedBard® tube may be modified for electrodes to be placed on the proximalside of the gastric balloon.

In all of the foregoing, a balloon is expanded to urge the electrodesagainst the mucosal tissue. While this is a presently preferredembodiment, any mechanism for urging the electrodes against the mucosaltissue may be used. In each of FIGS. 15 and 16, the tube 300′, 300″ isshown as it passes through the balloons 304′, 304″ and 309″. Thisillustration is made to indicate the tube passes through the balloonsand does terminate at the balloons. In fact, as the tube 300′, 300″passes through the balloons 304′, 304″ and 309″ it would be surroundedby the material of the balloons 304′, 304″ and 309″ and would not bevisible.

A still further embodiment is shown in FIG. 17. Instead of directlystimulating with current, the nerves are stimulated with magneticfields. In this case, the electrodes are coils 307′ insulated within theballoon 304′. The coils 307′″ create magnetic fields which inductivelycouple with the vagus nerves to create the blocking and stimulatingimpulses within the nerves.

b. Application to Acute Pancreatitis

When energized with a blocking frequency, the embodiment of FIG. 13 isuseful for treating acute or recurrent pancreatitis. This extremelyserious disease is characterized by an over-active pancreas whichexcretes digestive enzymes to such an extent that the pancreas itself isdigested. The disease can be extremely painful. In many cases, thedisease is fatal. The number of US patients who suffer an episode ofacute pancreatitis is approximately 185,000 annually. Baron, et al.,“Acute Necrotizing Pancreatitis”, New England J. of Medicine, Vol. 340,No. 18, pp. 1412-1417 (1999). This high incidence, coupled with the costand length of stay required, make the total cost of this disease tosociety enormous. No definitive therapy is currently available to treatthese patients except supportive care. Furthermore, the overallmortality rate for severe pancreatitis is about 20 to 30%. Id.

A recent study reported that the average total hospital cost to obtain asurvivor of severe, acute pancreatitis is nearly $130,000 with anaverage length of hospital stay of 40 days. Soran, et al., “Outcome andquality of life of patients with acute pancreatitis requiring intensivecare”, J. Surg. Res., 91(1), pp. 89-94 (2000). Further complicating themanagement of these patients is the uncertainty surrounding theprognosis because the course of the disease is unpredictable at initialpresentation. Chatzicostas, et al., “Balthazar computed tomographyseverity index is superior to Ranson criteria and APACHE II and IIscoring systems in predicting acute pancreatitis outcome”, J. ClinicalGastroenterology, 36(3), pp. 253-260 (2003). If patients could besuccessfully treated during the initial phases of the disease, with ahigher survival rate, there is a high probability of returning to aproductive life. Soran, et al., supra.

Pancreatitis may be associated with a number of etiologies includingchronic alcoholism or gallstones (e.g., gallstones lodged in thepancreatic or common duct). When acute pancreatitis becomes severe,treatment options are severely limited. Morbidity and mortality ratesfor pancreatitis are sobering. Baron, et al., “Acute NecrotizingPancreatitis”, New England J. of Medicine, Vol. 340, No. 18, pp.1412-1417 (1999) and Steer et al., “Chronic Pancreatitis”, New EnglandJ. of Medicine, pp. 1482-1490 (1995).

Down-regulating vagal activity can be used to treat pancreatitis. Arecently reported finding in experimental pancreatitis demonstrated thatthe vagus nerves are strongly implicated in the pathophysiology ofpancreatitis. Yoshinaga, et al., “Cholecystokinin Acts as an EssentialFactor in the Exacerbation of Pancreatic Bile Duct Ligation-Induced RatPancreatitis Model Under Non-Fasting Condition”, Japanese J. Pharmacol,Vol. 84, pp. 44-50 (2000). Pharmacologic means of decreasing pancreaticsecretion have been attempted with limited success because of thedose-limiting side effects encountered with the drugs, their lack ofspecificity or their lack of availability. In fact, one recent trial ofa specific blocker of parasympathetic (vagus nerves) control ofsecretion demonstrated a shortened recovery period in patients withacute pancreatitis while trials with other pancreatic down-regulatingdrugs that are less specific or potent have proven to be disappointing.Zapater, et al., “Do Muscarinic Receptors Play a Role in AcutePancreatitis?”, Clin. Drug Invest., 20(6), pp. 401-408 (2000); Norton,et al., “Optimizing Outcomes in Acute Pancreatitis”, Drugs, 61(11), pp.1581-1591 (2001). Atropine is a drug that blocks parasympathetic nerveendings. It is known to be desirable to use atropine in acutepancreatitis patients to down-regulate pancreatic activity.Unfortunately, for most such patients, this drug cannot be used due toits many side effects.

Acute pancreatitis patients may be placed on intravenous feeding withthe device 300 left in place for a chronic length of time (e.g., severaldays or weeks). At least the electrodes of the lower array 307 may beenergized with a blocking signal for the treatment of acutepancreatitis. The invention permits down-regulation of pancreatic outputthrough vagal blocking without the need for undesirable surgery fordirect vagal access.

In addition to utility for treating pancreatitis, the present inventionmay be used to avoid pancreatitis in patients having an increasedlikelihood of developing the disease. For example, patients undergoingendoscopic retrograde cholangiopancreatography (ERCP) and/or relatedprocedures are known to having a higher likelihood of developingpancreatitis. Such patients may be treated with the present inventionwith a blocking signal to down-regulate pancreatic output and reduce thelikelihood of developing pancreatitis.

Many physicians treating patients with pancreatitis use a nasogastrictube as part of the treatment. As a result, the present invention isillustrated as being incorporated on a nasogastric tube. However, asignificant body of physicians adheres to a belief that pancreatitispatients benefit from a feeding involving placing nourishment directlyinto the jejunum portion of the small intestine via a naso jejunal tube.While the present invention is illustrated in an embodiment of placementof the balloon and electrodes on a naso-gastric tube, the invention canalso be placed on a nasojejunal tube or a nasogastricjejunal tube.

c. Application to Ileus

With the device of FIGS. 12-16, the distal electrodes 307 may beenergized with a stimulation frequency as described for treatment ofileus. Post-trauma and post-surgery, patients may experience ileus whichis a dysfunction of the GI tract characterized in part by a lack ofmotility through the intestines. Prolonged ileus can result in stasisand serious infection. Kaiser, “Gallstone Ileus”, New England J. ofMedicine, Vol. 336, No. 12, pp. 879-880 (1997) (correspondence),Taguchi, et al., “Selective Postoperative Inhibition of GastrointestinalOpioid Receptors”, New England J. of Medicine, Vol. 345, No. 13, pp.935-940 (2001) and Steinbrook, “An Opioid Antagonist For PostoperativeIleus”, New England J. of Medicine, Vol. 345, No. 13, pp. 988-989 (2001)(Editorial).

Ileus patients commonly have nasogastric tubes as a regular part oftheir hospital stay. Without additional invasiveness, the presentinvention can be used as the nasogastric tube with the addition ofstimulation electrodes to stimulate the vagus to enhance motility.

The embodiment of FIG. 12 would permit the lower electrodes 307 to beenergized for stimulation frequency to treat ileus. Optionally, theupper electrodes 306 can be energized for blocking frequency if neededto prevent antidromic inhibitory responses or to prevent undesiredcardiac response.

The embodiment of FIG. 12-16 is useful to permit a diagnosis for asurgical implants as described in foregoing embodiments. Namely,responsiveness of a patient's gastro-intestinal symptoms (such as IBS)to the embodiment of FIG. 12 could justify a more invasive surgicalplacement of electrodes directly on the anterior or posterior vagusnerves.

In FIG. 15, a blocking or stimulating signal can be applied to theelectrode 305′. A blocking frequency is anticipated to be a therapeuticvalue for treating, for example, acute pancreatitis or an exacerbationof chronic pancreatitis. A stimulating frequency is anticipated to be oftherapeutic value for treating ileus. With the embodiment of FIG. 12,ileus, for example, can be treated by applying a stimulation frequencyto the lower electrode 307. A blocking frequency to the upper electrode306 can be used to block antidromic responses or to block adverse sideeffects of the stimulation signal on proximal organs (e.g., cardiacresponses).

4. Diagnostic Device

FIG. 18 illustrates a still further embodiment of the present inventionwhere a stimulating electrode 400 is placed near a distal end of anesophageal gastric duodenal (EGD) scope 402. Leads (not shown) passthrough the scope 402 connecting the electrode 400 to a controller (notshown).

Stimulation may be applied via the electrode 400 for transmucosalstimulation of an opposing vagus nerve (AVN in FIG. 18). Properplacement to achieve stimulation can be identified through thepreviously described techniques of identifying a cardiovascular responseto the stimulation indicating appropriate opposition of the electrode400 to a vagus nerve.

The scope may be left in place or may be removed by placing theelectrode attached to the mucosal wall (FIG. 19) through a pigtail orother attachment (such as an adhesive) with leads passing through thenostril or mouth. Alternatively, the electrode 400 may be kept in placepositioned underneath the mucosal layer and may be energized by radiofrequencies applied externally.

It will be appreciated that attachment of electrical apparatus tointernal mucosal layers of patients' is well known. Such a system isdescribed with respect to the Bravo™ pH monitoring system of Medtronic,Inc., Minneapolis, Minn., USA and as described in its product literatureUC 200300235 EN N15344 (2002) titled “Bravo™ pH Monitoring SystemCatheter-Free pH Testing”.

The foregoing embodiment is particularly useful for identifying patientsresponsive to blocking and stimulation as a diagnostic before applying amore invasive procedure using the blocking and stimulation apparatus andmethods described herein.

With the foregoing detailed description of the present invention, it hasbeen shown how the objects of the invention have been attained in apreferred manner. Modifications and equivalents of disclosed conceptssuch as those which might readily occur to one skilled in the art, areintended to be included in the scope of the claims which are appendedhereto.

We claim:
 1. A system for treating obesity comprising: a) a posteriorelectrode and an anterior electrode adapted to be placed on a vagusnerve at a subdiaphragmatic location; b) an implantable controllerelectrically connected to each of the posterior electrode and anteriorelectrode; the implantable controller comprising an induction coil, ananterior and a posterior electrical signal generator, a battery, and acentral processing unit comprising program storage and memory; c) anexternal controller comprising an external coil inductively coupled tothe induction coil, wherein the external controller is configured tocommunicate at least one parameter for a neural conduction blockingsignal to the implantable controller, wherein the at least one parameteris selected for the neural conduction blocking signal to i) at leastpartially downregulate the vagus nerve, ii) allow at least partialrecovery of the nerve activity following discontinuation of the neuralconduction blocking signal, and iii) reduce pancreatic and biliaryoutput via inhibition of pancreo-biliary output.
 2. The system of claim1, wherein the parameter is a frequency of at least 500 Hz.
 3. Thesystem of claim 2, wherein the parameter is application of the signalintermittently.
 4. The system of claim 1, wherein the central processingunit stores the at least one parameter.